Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit NeuroBiology of Diabetes, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Cell Metab. 2023 Mar 7;35(3):438-455.e7. doi: 10.1016/j.cmet.2023.02.004.
Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.
在绝经前，女性比男性更不易患代谢性疾病，这表明性激素具有保护作用。虽然已经证明雌激素和瘦素的中枢作用之间存在功能性协同作用，可以防止代谢紊乱，但介导这种串扰的潜在细胞和分子机制仍然难以捉摸。通过使用一系列胚胎期、成年期和组织/细胞特异性功能丧失型小鼠模型，我们记录了下丘脑 Cbp/P300 相互作用的转录激活因子与富含谷氨酸/天冬氨酸的羧基末端域 1（Cited1）在介导雌二醇（E2）依赖性瘦素作用方面的前所未有的作用，这些作用专门在促阿黑皮素原（Pomc）神经元中控制摄食。我们揭示了在弓状核 Pomc 神经元中，Cited1 通过作为一个共因子，通过直接的 Cited1-ERα-Stat3 相互作用汇聚 E2 和瘦素信号，从而驱动瘦素的厌食作用。这些结果为黑素细胞神经元如何通过 Cited1 整合来自性腺和脂肪轴的内分泌输入提供了新的见解，从而导致饮食诱导肥胖的性别二态性。
